- CO2-Enabled Cyanohydrin Synthesis and Facile Iterative Homologation Reactions**
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Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when a desired product is not accessible; one may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to accelerate cyanohydrin synthesis under neutral conditions with an insoluble cyanide source (KCN) without generating toxic HCN. Under inert atmosphere, the reaction is essentially not operative due to the unfavored equilibrium. The utility of CO2-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani–Fischer synthesis under neutral conditions. This protocol offers an easy access to a variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and an atmospheric pressure of CO2.
- Juhl, Martin,Petersen, Allan R.,Lee, Ji-Woong
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supporting information
p. 228 - 232
(2020/11/30)
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- 8-Hydroxyquinolin-2(1H)-one analogues as potential β2-agonists: Design, synthesis and activity study
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β2-Agonists that bind to plasmalemmal β2-adrenoceptors causing cAMP accumulation are widely used as bronchodilators in chronic respiratory diseases. Here, we designed and synthesized a group of 8-hydroxyquinolin-2(1H)-one analogues and studied their β2-agonistic activities with a cellular cAMP assay. Compounds B05 and C08 were identified as potent (EC50 2-agonists among the compounds tested. They behaved as partial β2-agonists in non-overexpressed HEK293 cells, and possessed rapid smooth muscle relaxant actions and long duration of action in isolated guinea pig tracheal strip preparations. In summary, B05 and C08 are β2-agonists with potential applicability in chronic respiratory diseases.
- Xing, Gang,Zhi, Zhengxing,Yi, Ce,Zou, Jitian,Jing, Xuefeng,Yiu-Ho Woo, Anthony,Lin, Bin,Pan, Li,Zhang, Yuyang,Cheng, Maosheng
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- Overcoming Selectivity Issues in Reversible Catalysis: A Transfer Hydrocyanation Exhibiting High Kinetic Control
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Reversible catalytic reactions operate under thermodynamic control, and thus, establishing a selective catalytic system poses a considerable challenge. Herein, we report a reversible transfer hydrocyanation protocol that exhibits high selectivity for the thermodynamically less favorable branched isomer. Selectivity is achieved by exploiting the lower barrier for C-CN oxidative addition and reductive elimination at benzylic positions in the absence of a cocatalytic Lewis acid. Through the design of a novel type of HCN donor, a practical, branched-selective, HCN-free transfer hydrocyanation was realized. The synthetically useful resolution of a mixture of branched and linear nitrile isomers was also demonstrated to underline the value of reversible and selective transfer reactions. In a broader context, this work demonstrates that high kinetic selectivity can be achieved in reversible transfer reactions, thus opening new horizons for their synthetic applications.
- Bhawal, Benjamin N.,Ehinger, Christian,Morandi, Bill,Reisenbauer, Julia C.
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supporting information
p. 10914 - 10920
(2020/07/13)
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- Nickel-Catalyzed Markovnikov Transfer Hydrocyanation in the Absence of Lewis Acid
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Hydrocyanation in the absence of toxic HCN gas is highly desirable. Addressing that challenge, transition-metal-catalyzed transfer hydrocyanation using safe HCN precursors has been developed, but these reagents generally require a Lewis acid for activation, and the control of regioselectivity often remains problematic. In this Letter, a Ni-catalyzed highly Markovnikov-selective transfer hydrocyanation that operates in the absence of any Lewis acid is reported. The readily prepared pro-aromatic 1-isopropylcyclohexa-2,5-diene-1-carbonitrile is used as the HCN source, and the reaction shows a broad substrate scope and high functional group tolerance. Terminal styrene derivatives, dienes, and internal alkynes are converted with good to excellent selectivities. Mechanistic studies provide insights into the origin of the regioselectivity.
- Frye, Nils L.,Bhunia, Anup,Studer, Armido
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supporting information
p. 4456 - 4460
(2020/06/03)
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- Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists
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A series of β2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β2-adrenoceptor and β1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β2-adrenoceptor agonistic effect with an EC50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β2-AR agonists.
- Yi, Ce,Xing, Gang,Wang, Siqi,Li, Xiaoran,Liu, Yichuang,Li, Jinyan,Lin, Bin,Woo, Anthony Yiu-Ho,Zhang, Yuyang,Pan, Li,Cheng, Maosheng
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- Adenosine receptor antagonists
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The invention provides a compound shown as a formula (I) and a pharmaceutical composition thereof. The compounds of formula (I) of the present invention are useful as adenosine receptor inhibitors, especially A2A and/or A2B inhibitors, for example, the product can be used for prevention or treatment of diseases associated with A2A and/or A2B activity or expression.
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Paragraph 0153-0155
(2020/12/15)
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- Identification of 2,6-Disubstituted 3 H-Imidazo[4,5- b]pyridines as Therapeutic Agents for Dysferlinopathies through Phenotypic Screening on Patient-Derived Induced Pluripotent Stem Cells
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Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to the lack of therapeutic agents. Herein, we report the design, synthesis, and structure-activity relationships of a 2,6-disubst
- Takada, Hiroyuki,Kaieda, Akira,Tawada, Michiko,Nagino, Tomoko,Sasa, Katsunori,Oikawa, Tatsuo,Oki, Akiko,Sameshima, Tomoya,Miyamoto, Kazumasa,Miyamoto, Makoto,Kokubu, Yuko,Tozawa, Ryuichi,Sakurai, Hidetoshi,Saito, Bunnai
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p. 9175 - 9187
(2019/10/17)
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- Transition-metal-free Intramolecular C-H amination of sulfamate esters and: N -alkylsulfamides
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The transition-metal-free intramolecular C-H amination of sulfamate esters using iodine oxidants, tert-butyl hypoiodite (t-BuOI) and N-iodosuccinimide (NIS) is reported. A method using NIS was also successfully applied to the oxidative cyclization of N-alkylsulfamides.
- Kiyokawa, Kensuke,Nakamura, Shogo,Jou, Keisuke,Iwaida, Kohji,Minakata, Satoshi
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supporting information
p. 11782 - 11785
(2019/10/02)
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- Process for the Catalytic Reversible Alkene-Nitrile Interconversion
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The present invention refers to processes for catalytic reversible alkene-nitrile interconversion through controllable HCN-free transfer hydrocyanation.
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Page/Page column 20; 21
(2017/09/02)
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- Efficient nickel-catalyzed hydrocyanation of alkenes using acetone cyanohydrin as a safer cyano source
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An active nickel catalyst prepared in situ from a Ni(II) compound, phosphine ligand, and zinc powder was found to be an efficient catalyst system for the hydrocyanation of various alkenes using acetone cyanohydrin as a safer cyano source. The combination of NiCl2·6H2O and 1,3-bis(diphenylphosphino)propane was the most efficient catalyst precursor in DMF. Under the optimized conditions, various styrenes, heterocyclic alkenes, and aliphatic alkenes were converted to their corresponding nitriles in excellent yields.
- Nemoto, Koji,Nagafuchi, Tsuyoshi,Tominaga, Ken-ichi,Sato, Kazuhiko
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p. 3199 - 3203
(2016/07/06)
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- Ametoctradin is a Potent Qo Site Inhibitor of the Mitochondrial Respiration Complex III
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Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Qo site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔGcal) of newly synthesized analogues as Qo site inhibitors correlated very well (R2 = 0.96) with their experimental binding free energies (ΔGexp). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor.
- Zhu, Xiaolei,Zhang, Mengmeng,Liu, Jingjing,Ge, Jingming,Yang, Guangfu
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p. 3377 - 3386
(2015/04/14)
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- Reductive Transformations of Carbonyl Compounds Catalyzed by Rhodium Supported on a Carbon Matrix by using Carbon Monoxide as a Deoxygenative Agent
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An efficient method for the rhodium on carbon matrix catalyzed preparation of secondary and tertiary amines, cyanoesters, and nitriles through the reductive amination/alkylation of carbonyl compounds was developed, including a convenient procedure for the tandem formal reductive addition of acetonitrile to aldehydes. The catalyst could be reused, and at least three consecutive reaction cycles were performed with comparable efficiency. The method was shown to be compatible with functional groups prone to reduction by hydrogen and complex hydrides. Beyond the matrix: An efficient method for the rhodium on carbon matrix catalyzed preparation of secondary and tertiary amines, cyanoesters, and nitriles through the reductive amination/alkylation of carbonyl compounds is developed, including a convenient procedure for the tandem formal reductive addition of acetonitrile to aldehydes. TON=turnover number.
- Yagafarov, Niyaz Z.,Usanov, Dmitry L.,Moskovets, Alexey P.,Kagramanov, Nikolai D.,Maleev, Victor I.,Chusov, Denis
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p. 2590 - 2593
(2015/09/15)
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- Activation of electrophilicity of stable Y-delocalized carbamate cations in intramolecular aromatic substitution reaction: Evidence for formation of diprotonated carbamates leading to generation of isocyanates
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Although cations with three heteroatoms, such as monoprotonated guanidine and urea, are stabilized by Y-shaped conjugation and such Y-conjugated cations are sufficiently basic to be further protonated (or protosolvated) to dications in strongly acid media, only O-monoprotonated species have been detected in the case of carbamates even in magic acid. We found that the trifluoromethanesulfonic acid-catalyzed cyclization of arylethylcarbamates proceeds to afford dihydroisoquinolones in high yield. In strong acids, methyl carbamates are fully O-monoprotonated, and these monocations do not undergo cyclization even under heating. But, as the acidity of the reaction medium is further increased, the cyclization reaction of methyl phenethylcarbamates starts to proceed as a first-order reaction, with a linear relationship between rate and acidity. The sign and magnitude of the entropy of activation ΔS ? were found to be similar to those of other AAc1 reactions. These results strongly support the idea that further protonation of the O-protonated carbamates is involved in the cyclization, but the concentration of the dications is very low and suggests that the rate-determining step is dissociation of methanol from the diprotonated carbamate to generate protonated isocyanate, which reacts with the aromatic ring. Therefore, O-protonated carbamates are weak bases in sharp contrast to other Y-shaped monocations.
- Kurouchi, Hiroaki,Kawamoto, Kyoko,Sugimoto, Hiromichi,Nakamura, Satoshi,Otani, Yuko,Ohwada, Tomohiko
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p. 9313 - 9328,16
(2012/12/11)
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- Monoalkylation of acetonitrile by primary alcohols catalyzed by iridium complexes
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The monoalkylation of acetonitrile by primary alcohols was achieved in a one-pot sequence in the presence of iridium catalysts. A diversity of nitriles has been obtained from aryl- and alkyl-methanols in excellent yield.
- Anxionnat, Bruno,Gomez Pardo, Domingo,Ricci, Gino,Cossy, Janine
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supporting information; experimental part
p. 4084 - 4087
(2011/09/21)
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- Direct transformation of N,N-disubstituted amides and isopropyl esters to nitriles
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Various N,N-dimethyl amides, N-methoxy-N-methyl amides, and isopropyl esters were smoothly transformed into the corresponding nitriles in good to moderate yields by the treatment with diisobutylaluminium hydride, followed by treatment with molecular iodine in aq ammonia. The present reactions are novel one-pot and practical methods for the transformation of N,N-disubstituted amides and isopropyl esters into nitriles, through the formation of hemiaminal O-AlBu2 and hemiacetal O-AlBu2, respectively.
- Suzuki, Yusuke,Yoshino, Takumi,Moriyama, Katsuhiko,Togo, Hideo
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experimental part
p. 3809 - 3814
(2011/06/25)
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- Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder
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A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P1′ and P2′ regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
- Pryde, David C.,Cook, Andrew S.,Burring, Denise J.,Jones, Lyn H.,Foll, Stephanie,Platts, Michelle Y.,Sanderson, Vivienne,Corless, Martin,Stobie, Alan,Middleton, Donald S.,Foster, Laura,Barker, Laura,Van Der Graaf, Piet,Stacey, Peter,Kohl, Christopher,Coggon, Sara,Beaumont, Kevin
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p. 142 - 159
(2007/10/03)
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- C-H activation reactions of ruthenium N-heterocyclic carbene complexes: Application in a catalytic tandem reaction involving C-C bond formation from alcohols
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A series of ruthenium hydride N-alkyl heterocyclic carbene complexes has been investigated as catalysts for a tandem oxidation/Wittig/reduction reaction to give C-C bonds from alcohols. The C-H-activated carbene complex Ru(I iPr2Me2)′(PPh3) 2(CO)H (9) proves to be the most active precursor catalyzing the reaction of PhCH2OH and Ph3P=CHCN in 3 h at 70 °C. These results provide (a) a rare case in which N-alkyl carbenes afford higher catalytic activity than their N-aryl counterparts and (b) a novel example of the importance of NHC C-H activation in a catalytic cycle.
- Burling, Suzanne,Paine, Belinda M.,Nama, Devendrababu,Brown, Victoria S.,Mahon, Mary F.,Prior, Timothy J.,Pregosin, Paul S.,Whittlesey, Michael K.,Williams, Jonathan M. J.
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p. 1987 - 1995
(2007/10/03)
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- Highly efficient conjugate reduction of α,β-unsaturated nitriles catalyzed by copper/xanthene-type bisphosphine complexes
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α,β-Unsaturated nitriles are chemoselectively reduced to the corresponding saturated nitriles in high yields using a copper-DPEphos or Xantphos complex as catalyst in the presence of polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent and t-butanol as additive. The Royal Society of Chemistry 2005.
- Kim, Daesung,Park, Bu-Mahn,Yun, Jaesook
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p. 1755 - 1757
(2007/10/03)
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